Targeting Persistence: The Next Frontier in TB Drug Development

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As if it werent bad enough that tuberculosis affects a third of the world's population, 99.5% of those cases, or roughly 1.8 billion people, exhibit no outward symptoms of infection. They have a latent form of the disease. It sounds almost benign, but the reality is that the bacterium that causes the active disease -- Mycobacterium tuberculosis or M.Tb persists in their lungs, cleverly concealed and notoriously hard to detect.

The persistence of M.Tb helps explain why TB has been so difficult to treat effectively. Each year, 8 million people who carry "latent" disease will experience reactivation of their disease to full-blown pulmonary tuberculosis. Only 27% of the world's TB patients are fully and properly treated. Even if they are lucky enough to finish treatment, some 5-20% of these patients will go on to experience a reactivation of disease. Most people don't know that they are not completely "cured" and that persistent bacteria can linger even after treatment with current drugs. Due to the large number of latent cases, reactivation is one of the most common ways the disease spreads from one person to another.

Since M.Tb was first identified, scientists have wrestled with its unusual ability to persist in a non-replicating state. It creates a problem for traditional antibiotics and raises some vexing questions: What is the bug doing in a persistent state? What causes it to go "active"? How critical is the immune system response? Perhaps most importantly, how can we begin to answer these questions?

These questions underscore the need for more basic research to address the complex biology of persistent M.Tb during latent disease. At the same time, it's been noted that persistent bacteria seem to play a role in both active and latent disease. Most antibiotics only target bacteria inside the body that are actively replicating. With tuberculosis, however, the bulk of infecting bacteria persist without replicating and live inside the very cells designed to destroy the disease. That makes it difficult to determine whether a patient is free from the disease. Furthermore, if a particular patient suffers another bout of TB symptoms, one cant be sure if it's a reactivation of persistent bacteria or a wholly new infection.

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A Drug Strategy for Latency

A drug that targets latent disease is critical to improved therapy, reducing the spread of disease, and ultimately reversing the TB epidemic. However, latent disease poses a number of challenges to scientists trying to develop new drugs. One possible approach to targeting the persistent bacteria -- without waiting for the basic science to get up to speed -- is to work on developing a new, faster-acting treatment for the latent bacteria in patients with active tuberculosis. Research to date suggests that persistent bacteria behave similarly in both active and latent cases. The hope is that drugs developed to fight persistent bacteria will ultimately prove effective in treating latent disease.

Another clue supporting the validity of this approach is that research suggests that drugs that most effectively shorten TB therapy are most effective at attacking persistent M.Tb. Faster-acting drugs will offer benefits far beyond pointing the way to therapies aimed at latent disease. Drugs that need to be taken for relatively short periods of time will also ensure that more patients receive proper treatment, while reducing the associated healthcare expenses by up to 65%. Equally important, the shorter treatment duration will make it easier for people to see therapy through to the end. This will increase the likelihood of full compliance, limiting the opportunity for the bacteria to evolve beyond antibiotics' reach.

The Global Alliance for TB Drug Development is building a portfolio of promising drug candidates and creating partnerships in order to deliver a new anti- tuberculosis drug in a decade. A key part of the R&D strategy of the TB Alliance is to promote a productive environment for new TB research and drug development. For more about the Alliance: www.tballiance.org.

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